Long-term potentiation depends on release of D-serine from astrocytes.

Henneberger C, Papouin T, Oliet SH, Rusakov DA - Nature (2010)

Bottom Line:
Furthermore, loading an astrocyte with exogenous Ca(2+) buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned.This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP.We therefore demonstrate that Ca(2+)-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.

Affiliation: UCL Institute of Neurology, University College London, London WC1N 3BG, UK.

ABSTRACTLong-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory. The classical form of LTP relies on N-methyl-D-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca(2+)-dependent release of the NMDAR co-agonist D-serine. Release of D-serine from glia enables LTP in cultures and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus. However, increases in Ca(2+) concentration in astroglia can also release other signalling molecules, most prominently glutamate, ATP and tumour necrosis factor-alpha, whereas neurons themselves can synthesize and supply D-serine. Furthermore, loading an astrocyte with exogenous Ca(2+) buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca(2+) in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca(2+)-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.

Mentions:
If astrocytes enable LTP induction by increasing activation of the NMDAR co-agonist site then reducing the site availability should prevent LTP25. To replicate the ~25% decrease of NMDAR responses under astrocytic Ca2+ clamp (Fig. 2a-b), we used the selective NMDAR glycine site blocker 5,7-dichlorokynurenic acid (DCKA) at 750 nM (Fig. 3a and Supplementary Fig. 8). Strikingly, 750 nM DCKA abolished LTP just as did 50 μM APV (Fig. 3a). Consistent both with these observations and with the Ca2+ clamp effects, FAC also reduced NMDAR fEPSPs by 23 ± 4% (n = 16, p = 0.00017; Supplementary Fig. 9a-b) and blocked LTP in a D-serine-sensitive manner (Fig. 3b-c). Although the mechanisms and specificity of FAC actions are incompletely understood, we confirmed that the effect of FAC on NMDAR fEPSPs (i) paralleled that on LTP (Supplementary Fig. 9c-d), (ii) was absent in glycine, and (iii) did not involve changes in release probability or axonal excitability (Supplementary Fig. 10).

Mentions:
If astrocytes enable LTP induction by increasing activation of the NMDAR co-agonist site then reducing the site availability should prevent LTP25. To replicate the ~25% decrease of NMDAR responses under astrocytic Ca2+ clamp (Fig. 2a-b), we used the selective NMDAR glycine site blocker 5,7-dichlorokynurenic acid (DCKA) at 750 nM (Fig. 3a and Supplementary Fig. 8). Strikingly, 750 nM DCKA abolished LTP just as did 50 μM APV (Fig. 3a). Consistent both with these observations and with the Ca2+ clamp effects, FAC also reduced NMDAR fEPSPs by 23 ± 4% (n = 16, p = 0.00017; Supplementary Fig. 9a-b) and blocked LTP in a D-serine-sensitive manner (Fig. 3b-c). Although the mechanisms and specificity of FAC actions are incompletely understood, we confirmed that the effect of FAC on NMDAR fEPSPs (i) paralleled that on LTP (Supplementary Fig. 9c-d), (ii) was absent in glycine, and (iii) did not involve changes in release probability or axonal excitability (Supplementary Fig. 10).

Bottom Line:
Furthermore, loading an astrocyte with exogenous Ca(2+) buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned.This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP.We therefore demonstrate that Ca(2+)-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.

Affiliation:
UCL Institute of Neurology, University College London, London WC1N 3BG, UK.

ABSTRACTLong-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory. The classical form of LTP relies on N-methyl-D-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca(2+)-dependent release of the NMDAR co-agonist D-serine. Release of D-serine from glia enables LTP in cultures and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus. However, increases in Ca(2+) concentration in astroglia can also release other signalling molecules, most prominently glutamate, ATP and tumour necrosis factor-alpha, whereas neurons themselves can synthesize and supply D-serine. Furthermore, loading an astrocyte with exogenous Ca(2+) buffers does not suppress LTP in hippocampal area CA1 (refs 14-16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca(2+) in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous D-serine or glycine, whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca(2+)-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.